*Pediatric Gastroenterology, USA
†Department of Pathology and Department of Pediatrics, USA
‡Department of Pediatrics and Recanati Miller Transplantation Institute, Mount Sinai School of Medicine, New York, USA
§Department of Infectious Diseases, Queens Hospital Center, Queens, NY, USA.
Received 10 December, 2008
Accepted 24 March, 2009
Address correspondence and reprint requests to Israel Kochin, MD, Pediatric Liver & Liver Transplantation, Mt Sinai Medical Center, One Gustave L. Levy Place, Box 1104, New York, NY 10029 (e-mail: email@example.com).
The authors report no conflicts of interest.
Variceal bleeding due to elevated portal venous pressure may result from both cirrhotic and noncirrhotic processes. Etiologies of portal hypertension in the absence of cirrhosis include portal vein thrombosis, nodular regenerative hyperplasia (NRH), hepatoportal sclerosis (HPS), incomplete septal cirrhosis, schistosomiasis, and vasculitides (1). HPS is also known as Banti syndrome (2), idiopathic portal hypertension, and noncirrhotic portal fibrosis. Characteristic histological findings are narrowed and/or obliterated portal veins, often with dilated periportal megasinusoids (1,3). Patients with HPS often present with variceal bleeding, splenomegaly, thrombocytopenia, and only mildly abnormal liver function tests (1,3). NRH is often the result of disturbed portal venous circulation and is characterized histologically by multiple small nodules composed of hyperplastic hepatocytes often arranged in cords more than 2 cells thick, typically surrounding portal regions. Hepatocytes located between the nodules are frequently atrophic and compressed but without significant fibrosis (4). NRH may be associated with medications (6-thioguanine, highly active antiretroviral therapy [HAART] with nucleoside reverse transcriptase inhibitors) and viral infections, including hepatitis C and HIV (1,4). NRH may also be seen in the setting of HPS and recently 4 adults with HIV on HAART with noncirrhotic portal hypertension were found to have HPS (1). We describe the first pediatric case of a 15-year-old boy with HIV on HAART with HPS and NRH.
A 15-year-old Hispanic boy with a history of perinatally acquired HIV presented to a local emergency room with a 1-day history of hematemesis and hematochezia along with a feeling of lightheadedness. He had also experienced abdominal pain that resolved with vomiting. HIV was diagnosed at 2 months of age after both parents had been known to have HIV. The growth and development were normal and HAART therapy commenced at 7 years of age because of decreased CD4 count of 217/mm3. His medication regimen is described in Table 1 and the cumulative drug exposure in Table 2. His viral load remained relatively low (range <50–4154 copies/mL), but his CD4 count also remained low (108–235/mm3). He admitted to intermittent noncompliance with HAART medications.
He had been in good health with normal levels of activity. He had not recently experienced melena, fever, pain, pruritis, weight loss, or lethargy and denied consuming alcoholic beverages. Two years before the onset of hematemesis an enlarged spleen at 3 to 4 cm below the costal margin and thrombocytopenia (73,000–104,000 platelets/mm3) were noted. His liver function tests had been only modestly elevated on occasion, with a peak alanine aminotransferase of 60 IU/mL and aspartate aminotransferase 75 IU/mL at age 13 years. His only other prior hospitalizations had been at 4 weeks of age for fever and at 5 months of age for pneumonia. He had no personal or family history of liver disease, obesity, or thrombotic events. His mother died when he was 5 years old of an AIDS-related illness, and his father is HIV seropositive and is currently well without antiretroviral therapy.
Upon presentation, his blood pressure was 113/54 mmHg, pulse was 107 beats per minute, respirations were 20/minute, and body mass index was 19 kg/m2. His spleen was palpable at 6 cm below the left costal margin and his liver was not enlarged. He did not have jaundice, encephalopathy, ascites, or other stigmata of chronic liver disease. Laboratory investigations revealed a white blood cell count of 4800/mm3, hemoglobin 6.6 g/dL, platelet count 72,000/mm3, international normalized ratio of 1.6, total bilirubin 2.1 mg/dL, direct bilirubin 0.5 mg/dL, albumin 2.6 g/dL, serum alanine aminotransferase 22 IU/L, serum aspartate aminotransferase 38 IU/L, γ-glutamyl transferase 12 IU/L, and alkaline phosphate 169 IU/L. Serological evaluation for hepatitis A, B, and C was negative. Epstein-Barr virus polymerase chain reactionwas 714 copies/105 lymphocytes. Cytomegalovirus was undetectable by polymerase chain reaction. Tests for anti-nuclear, anti-smooth muscle, and anti-liver kidney microsomal antibody were negative. α-1 antitrypsin phenotype was MM and ceruloplasmin was normal. α-Fetoprotein was 1.5 ng/mL. HIV viral load was 61 copies per milliliter with a CD4 count of 100/mm3. D-dimers were mildly elevated at 2.4 μg/mL (normal <0.5 μg/mL). Serum blood urea nitrogen and creatinine were normal. He was treated with intravenous fluids and transfused with packed red blood cells.
Ultrasonogram demonstrated a small-coarsened liver and splenomegaly (22-cm span) with an echogenic pancreas. Recanalization of the paraumbilical vein was present, although the portal system was not well visualized. Magnetic resonance imaging revealed a small heterogenous liver with diminutive right hepatic lobe and dominant left hepatic lobe with multiple small sclerotic nodules. A possibly chronically thrombosed and recannulated right branch of the portal vein was described. Paraesophageal, perigastric, perisplenic, and anterior abdominal varices as well as ascites were also noted. Hypercoagulability studies demonstrated mild decreases in protein C (antigen and function both 64% of normal) and protein S antigen (total and free were 58% and 47% of normal). No significant abnormalities of homocysteine, activated protein C resistance, antithrombin III, or antibodies to cardiolipin were detected. Genetic analysis did not reveal a Factor V Leiden, 5,10-methylenetetrahydrofolate reductase, or prothrombin genetic mutations predisposing to thrombosis.
Esophagogastroduodenoscopy revealed multiple-grade 3 esophageal varices with red wales and portal gastropathy without active bleeding. Sclerotherapy was performed with sodium morrhuate. Antiretroviral therapy was held, and an ultrasonographically guided liver biopsy after receiving fresh frozen plasma to correct coagulopathy was performed. The liver biopsy showed mild portal fibrosis with occasional septum formation. The portal venous branches were narrowed and atrophic. Rare periportal megasinusoids were also present (Fig. 1). These findings were diagnostic for hepatoportal sclerosis. Also, periportal regions of hepatocytic hyperplasia were separated by narrow centrilobular zones of atrophy with sinusoidal dilatation (Fig. 2), consistent with nodular regenerative hyperplasia. Furthermore, both mild micro- and macrovesicular steatosis were also focally observed. Stains for pathogenic organisms were negative and viral inclusions were not present.
For portal hypertension, the patient was treated with propranolol with appropriate dosage increases on an interval basis and also given iron for anemia. Since discharge he has been well and has not had hematochezia, melena, or hematemesis. He was restarted on HAART regimen of tenofovir, emtricitabine, darunavir/ritonavir, and raltegravir with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia prophylaxis 2 months after discharge. Four subsequent endoscopies with variceal banding were performed during an 11-month period. Interval decreases in both the number and size of esophageal varices were evident, with the most recent endoscopy demonstrating no more than grade 1 to 2 esophageal varices, although portal gastropathy was still visible. At last follow-up the platelet count was 91,000/mm3, international normalized ratio 1.4, albumin 3.5 g/dL, total bilirubin 1.8 mg/dL, direct bilirubin 0.4 mg/dL, and transaminases normal. He continues to be followed closely for any elevation of liver transaminases, reduced hepatic function, or elevated α-fetoprotein as well as regular imaging of his liver to monitor for lesions suspicious for hepatocellular carcinoma or alterations in hepatic vascular flow.
Acute hepatitis, giant cell hepatitis, infection with hepatotropic viruses (hepatitis B virus, hepatitis C virus), and opportunistic pathogens have been recognized in children with the later stages of HIV infection (5). A chronic and subclinical hepatotoxicity of the nucleoside reverse transcriptase inhibitors didanosine and stavudine and the nonnucleoside reverse transcriptase inhibitor nevirapine has been reported to occur in approximately 2% to 18% of treated patients and is associated with duration of therapy (6). Hepatic dysfunction may range from minimal to liver failure, and interruption of treatment may be necessary (7). HIV-associated malignancy may contribute to liver disease. The HIV virus has been speculated to directly induce a hypercoagulable state through activation of endothelial cells and decreased hepatic production of anticoagulant factors, and induce cryptogenic liver disease such as HPS and NRH (8).
HPS and NRH may share a common mechanistic pathway of compromised intrahepatic portal venous flow (3,4). The histological appearance of HPS includes subintimal fibrosis of small portal venous branches with thickening of the venous walls, and dilatation of sinusoids (megasinusoids) without cirrhosis (1). Identified associations with HPS include spherocytosis, neonatal omphalitis, neonatal umbilical catheterization, extrahepatic portal vein thrombosis, and right kidney agenesis (3). Cytotoxic agents such as azathioprine, thioguanine, chlorambucil, busulphan, vinyl chloride, arsenic, and vitamin A have also been associated with HPS (9). NRH is characterized by multiple small hyperplastic nodules centered around portal tracts compressing adjacent, frequently atrophic liver cells and sinusoids without significant fibrosis (4). NRH may be associated with infection (HIV, tuberculosis, and HCV), cardiac, rheumatologic, hematological, hypercoagulable states, drugs (steroids, oral contraceptives, and HAART), primary biliary cirrhosis, Turner syndrome, and renal and bone marrow/stem cell transplantation (4,8). NRH may occur with partial or complete portal vein obstruction secondary to ischemia and reactive hepatocyte proliferation because of compensatory hepatic arterial blood flow (4).
NRH with associated findings of perisinusoidal or portal fibrosis was recently described in adults on HAART (8,10). Hepatoportal sclerosis was also recently reported in 4 adults presenting with variceal bleeding from portal hypertension on HAART (1). This may be a direct acute hepatotoxic effect of antiretroviral agents or the HIV virus inducing hepatotoxicity, intrahepatic endothelial damage, and a prothrombotic state, and/or alter hepatic fibrinogenesis leading to NRH and/or HPS (1,8,11). The exact mechanism of toxicity from HAART has not been elucidated and is speculated to occur secondary to mitochondrial damage and/or immune reconstitution from hepatic neoantigens created by exposure to reactive drug metabolites (1,6). Although the patient admitted to intermittent noncompliance, basing his exposure on his prescribed HAART regimen (Table 1) indicates prolonged exposure to didanosine, emtricitabine, stavudine, and zidovudine, which are considered to have relatively more hepatotoxic profiles than other medications from his HAART regimen (6). Although it is difficult to determine relative contributions of a particular drug, duration of exposure is a risk factor for the development of hepatotoxicity for some HAART medications (1,6).
Histological obliteration of portal vasculature resulting in HPS and NRH may be due to microthrombosis or macrothrombosis of the right portal vein from inherited protein C or protein S deficiency. Alternatively, coagulation defects leading to thrombosis may be secondary to progressive liver disease and/or represent altered homeostatic coagulatory balance (11). Repeated episodes of pylephlebitis and septic microthrombophlebitis may contribute to the obliteration of portal microvasculature in immunocompromised individuals (12), although this process was not demonstrated here. Liver biopsy in this patient also revealed hepatic steatosis, which is associated with a more rapidly progressing hepatic fibrosis (1). The hypoalbuminemia that subsequently normalized was perhaps a consequence of variceal bleeding. The prolonged modest elevation of total bilirubin may represent hemolysis, decreased hepatic bilirubin clearance as a result of impairment of bilirubin conjugation, or both, which is frequently seen in patients taking HAART and is likely to be of little consequence (6,13).
Management of HPS includes therapy treating portal hypertension and withdrawal of precipitating factors such as hepatotoxic medications. HPS should be considered in the differential diagnosis of patients with variceal bleeding from noncirrhotic portal hypertension, although HPS may be difficult to diagnose even with small needle liver biopsy (1). Secondary prophylaxis following an esophageal variceal bleed includes the use of nonselective β-blockers, endoscopic variceal ligation or sclerotherapy, and shunting via transjugular intrahepatic portosystemic shunts, or surgical shunting (14). The lack of randomized controlled trials evaluating different treatment options for pediatric portal hypertension makes consensus approach difficult. The patient underwent combination therapy with banding and nonselective β-blockers; this strategy has been shown to be superior to banding alone for protection against rebleeding (15). Liver transplantation is feasible in HIV-infected patients with complications of refractory severe portal hypertension and survival was comparable in HIV and non-HIV recipients; however, patients with HIV had significantly higher mortality from infectious complications (16). After liver transplant HAART therapy remains necessary because HIV infection is unresolved; recurrence of NRH has been described after transplant in HIV-infected individuals (10).
In summary, we describe a 15-year-old boy with HIV on HAART who presented with variceal bleeding and was found to have hepatoportal sclerosis with nodular regenerative hyperplasia on liver biopsy. He responded well to endoscopic and medical treatment of portal hypertension. To our knowledge, this is the first report of a child or adolescent with HIV also diagnosed as having hepatoportal sclerosis. There may be an association of prolonged antiretroviral therapy with the development of HPS, although an exact etiology remains elusive. Patients with HIV should be monitored for subtle signs of portal hypertension and HPS should be considered in the differential diagnosis of patients with HIV who develop portal hypertension.
1. Schiano TD, Kotler DP, Ferran E, et al
. Hepatoportal sclerosis as a cause of noncirrhotic portal hypertension in patients with HIV. Am J Gastroenterol 2007; 102:2536–2540.
2. Cordeau MP, Prosmanne O, Robillard P. Case of the day. Noncirrhotic idiopathic portal hypertension (Banti syndrome). Radiographics 1990; 10:114–116.
3. Maksoud JG, Mies S, da Costa Gayotto LC. Hepatoportal sclerosis in childhood. Am J Surg 1986; 151:484–488.
4. Geller SA, Dubinsky MC, Poordad FF, et al
. Early hepatic nodular hyperplasia and submicroscopic fibrosis associated with 6-thioguanine therapy in inflammatory bowel disease. Am J Surg Pathol 2004; 28:1204–1211.
5. Lacaille F, Fournet JC, Blanche S. Clinical utility of liver biopsy in children with acquired immunodeficiency syndrome. Pediatr Infect Dis J 1999; 18:143–147.
6. Nunez M. Hepatotoxicity of antiretrovirals: incidence, mechanisms and management. J Hepatol 2006; 44:S132–139.
7. Maida I, Garcia-Gasco P, Sotgiu G, et al
. Antiretroviral-associated portal hypertension: a new clinical condition? Prevalence, predictors and outcome. Antivir Ther 2008; 13:103–107.
8. Mallet V, Blanchard P, Verkarre V, et al
. Nodular regenerative hyperplasia is a new cause of chronic liver disease in HIV-infected patients. Aids 2007; 21:187–192.
9. Shepherd P, Harrison DJ. Idiopathic portal hypertension associated with cytotoxic drugs. J Clin Pathol 1990; 43:206–210.
10. Tateo M, Sebagh M, Bralet MP, et al
. A new indication for liver transplantation: nodular regenerative hyperplasia in human immunodeficiency virus-infected patients. Liver Transpl 2008; 14:1194–1198.
11. Tripodi A, Salerno F, Chantarangkul V, et al
. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 2005; 41:553–558.
12. Maida I, Nunez M, Rios MJ, et al
. Severe liver disease associated with prolonged exposure to antiretroviral drugs. J Acquir Immune Defic Syndr 2006; 42:177–182.
13. Korenblat KM, Berk PD. Hyperbilirubinemia in the setting of antiviral therapy. Clin Gastroenterol Hepatol 2005; 3:303–310.
14. Garcia-Tsao G, Sanyal AJ, Grace ND, et al
. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007; 46:922–938.
15. de la Pena J, Brullet E, Sanchez-Hernandez E, et al
. Variceal ligation plus nadolol compared with ligation for prophylaxis of variceal rebleeding: a multicenter trial. Hepatology 2005; 41:572–578.
16. Schreibman I, Gaynor JJ, Jayaweera D, et al
. Outcomes after orthotopic liver transplantation in 15 HIV-infected patients. Transplantation 2007; 84:697–705.
© 2010 Lippincott Williams & Wilkins, Inc.